The primary objectives of this project concern the pathogenesis of alterations in biliary secretion and hepatic injuries induced by bile salts and the heaptic uptake, transport and secretion of bile salts and their relationship to hepatic pathophysiology. Studies during the past year produced the following results: the bile canaliculus is the principal subcellular structure affected in the acute cholestasis induced by 3 beta hydroxycholenoate (BHC) as well as taurolithocholate (TLC); cholersis induced by taurocholate (TC) or dehydrocholate (DHC) was not associated with any noteworthy ultrastructural changes; TC administered with TLC reverses the cholestasis and ultrastructural changes induced by TLC, but DHC does not overcome these effects of TLC; structural changes associated with cholestasis induced by these bile salts are more severe in the periportal region of the hepatic lobule. These results suggest that TLC and BHC induce cholestasis by primarily affecting the structural and functional integrity of the bile canalicular membrane. The contrasting effects of TC and DHC on the RLC-induced cholestasis suggest that TC overcomes the effects of TLC by solubilizing the latter into mixed micelles, but DHC has little or no such effect. The intralobular variation in severity of subcellular injuries may reflect the accumulation of bile salts in greater concentrations in the periportal region. In addition, methods which would enable morphological studies of bile salts in the tissue are being developed.